Dourif was born in Huntington, West Virginia, on March 18, 1950, one of six children born to Joan Mavis Felton (née Bradford), an actress, and Jean Henri Dourif, an art collector who owned and operated a dye factory.
His paternal grandparents emigrated from France, and his paternal grandfather co-founded the Standard Ultramarine and Color Company in Huntington. After Dourif's father died in 1953, his mother remarried champion golfer William C. Campbell, who helped raise Dourif and his five siblings (four sisters and one brother). From 1963 to 1965, Dourif attended the private Aiken Preparatory School in Aiken, South Carolina. There, he pursued his interests in art and acting. Although he briefly considered becoming a flower arranger, he was eventually inspired to become an actor by his mother's participation as an actress in a community theater called "Give me Shelter".
After Aiken, he attended Fountain Valley School in Colorado Springs, Colorado, graduating in 1968. Dourif attended Marshall University for a time, before quitting college and moving to New York City to study acting on the advice of actress Conchata Ferrell.
Starting in school productions, Dourif progressed to community theater, joining up with the Huntington Community Players while attending Marshall University. In New York City, he studied with Sanford Meisner, and worked with Marshall Mason and Lanford Wilson at the Circle Repertory Company. During the early 1970s, Dourif appeared in a number of plays, off-Broadway and at Woodstock, New York, including The Ghost Sonata, The Doctor in Spite of Himself, and When You Comin' Back, Red Ryder?, in which he was spotted by director Miloš Forman who cast him in One Flew Over the Cuckoo's Nest (1975).
In 2013, after a three-decade absence from the stage, Dourif chose to star alongside Amanda Plummer in the Off-Broadway revival of Tennessee Williams' The Two-Character Play that played to critical acclaim at the New World Stages. He explained, in a filmed interview released by the producers, why he broke his 29-year hiatus from acting in live theater: "I hated the stage, did not want to do it. And then somebody said, 'Will you do a play? It's with Amanda Plummer', and I said, 'Oh shit! No. Oh God, I'm gonna have to do this...'". It opened on June 10, 2013 and closed on September 29, 2013. The play was subject to a number of performance cancellations, one relating to Dourif's absence, due to a death in the family. Plummer refused to perform without Dourif, notwithstanding the presence of an understudy.
Although One Flew Over the Cuckoo's Nest is frequently cited as Dourif's film debut, his first acting for screen was in a low-budget film called Split, which was never released. He followed this with a part in the 1975 film W.W. and the Dixie Dancekings, but his bit part was omitted from the final cut of the film. His portrayal of the vulnerable Billy Bibbit in Cuckoo's Nest ended up being his big break, earning him a Golden Globe Award (Best Actor Debut) and a British Academy Award (Supporting Actor) as well as a nomination for Academy Award for Best Supporting Actor.
In 1981, Vincent Canby listed Dourif as one of twelve actors to watch, calling Dourif "one of the most intense, most interesting young film actors of his generation." Skeptical of his instant stardom, Dourif returned to New York, where he continued in theater and taught acting and directing classes at Columbia University until 1988, when he moved to Hollywood.
Dourif has often played eccentric or disturbed characters, starting with Cuckoo's Nest and continuing with Eyes of Laura Mars (1978), John Huston's Wise Blood (1979), Forman's Ragtime (1981), Marc Didden's Istanbul (1985) and David Lynch's Dune (1984) and Blue Velvet (1986).
Dourif has appeared in a number of horror films, notably as the voice of Chucky in the Chucky franchise. He portrayed the Gemini Killer in The Exorcist III (1990) and appeared in Death Machine (1994) and Alien: Resurrection (1997). He later appeared as Sheriff Lee Brackett in Rob Zombie's Halloween (2007) and Halloween II (2009). In 2013, Dourif reprised his role as the voice of Chucky in the sixth installment of the Child's Play franchise, Curse of Chucky, which was a straight-to-DVD release. His daughter, Fiona Dourif, also starred with him.
Other notable film roles include Gríma Wormtongue in the Lord of the Rings trilogy and supporting roles in Fatal Beauty (1987), Mississippi Burning (1988), Hidden Agenda (1990), London Kills Me (1991) and Sinner (2007).
Dourif was initially cast as the Scarecrow in Batman Forever (1995) while Tim Burton was attached to the project. However, Joel Schumacher eventually took over the project and instead cast Tommy Lee Jones as Two-Face and Jim Carrey as the Riddler.
In 1984, Dourif played a suspected serial killer in the episode "Number Eight" of Tales of the Unexpected. In 1994, he appeared in The X-Files episode "Beyond the Sea" as the psychic serial killer Luther Lee Boggs. He also portrayed Lon Suder in a three episode story arc on Star Trek: Voyager and guest starred as a troubled monk haunted by visions in Babylon 5. Dourif later gained acclaim as Doc Cochran in Deadwood, receiving a 2004 Emmy Award nomination for "Outstanding Supporting Actor in a Drama Series."
In 2011, he guest starred in the third-season finale of Fringe and in 2014 he made a brief cameo in the Agents of S.H.I.E.L.D. episode "The End of the Beginning."
In 2012, Dourif contributed spoken word vocals to three songs on the album Misery Together by the Norwegian duo Thinguma*jigSaw. Dourif also appears in the music videos for "Stranger in Town" (1984) by Toto and "Drinking from the Bottle" (2012) by Calvin Harris.
Dourif has been married twice. He has one daughter, Fiona, with his former wife Joni, and adopted Joni's daughter, Kristina Dourif Tanoue.